We report the forensic case of a 42-year-old man, a known drug user, who died at home and whose body was only discovered 2 months later. Autopsy was performed on a corpse in the late postmortem stage where no apparent cause of death was found. A toxicological screening of biological materials (blood, urine and gastric content) using liquid chromatography with different types of mass detection (ion trap and high-resolution) revealed the presence of methoxetamine (MXE), a ketamine analog, and its metabolites. MXE and a number of its metabolites (e.g., O-desmethyl, N-desethyl, hydroxy, glucuronides and sulfates) were identified in urine. Based on the results, a method using liquid chromatography with tandem mass spectrometry was developed and validated for the determination of MXE concentration in biological materials. The following values of MXE concentration were found: blood-3.6 ng/mL, urine-70.5 ng/mL and gastric content-18.0 ng/mL. Given the absence of other drugs, medications and poisons, it can be inferred that despite relatively low blood concentrations, MXE contributed to the victim's death. The present case demonstrates that even after 2 months, MXE and its several metabolites can be detected and determined in the human cadaver at a relatively advanced stage of decomposition.
- MeSH
- cyklohexanony * analýza metabolismus MeSH
- cyklohexylaminy * MeSH
- dospělí MeSH
- lidé MeSH
- mrtvola MeSH
- pitva MeSH
- tělesné tekutiny * metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Klíčová slova
- Orfadin,
- MeSH
- benzoáty terapeutické užití MeSH
- biologické markery MeSH
- cyklohexanony terapeutické užití MeSH
- dieta MeSH
- genetické testování metody využití MeSH
- hepatocelulární karcinom terapie MeSH
- hypoglykemie diagnóza terapie MeSH
- klinický obraz nemoci MeSH
- kojenec MeSH
- komorbidita MeSH
- lidé MeSH
- prognóza MeSH
- statistika jako téma MeSH
- transplantace jater * MeSH
- tyrosinemie * diagnóza genetika terapie MeSH
- ultrasonografie metody využití MeSH
- vrozené poruchy metabolismu diagnóza etiologie genetika MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Cancer cells generally possess higher levels of reactive oxygen species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p-coumaric acid methyl ester (pcm) revealed a new antitumor lead, graviquinone. Graviquinone bypassed ABCB1-mediated resistance, induced DNA damage in lung carcinoma cells but exerted DNA protective activity in normal keratinocytes, and modulated DNA damage response in MCF-7 cells. The cytotoxic effect of pcm in MCF-7 cells was potentiated under H2O2-induced oxidative stress, and the formation of graviquinone was confirmed by Fenton's reaction on pcm. In silico density functional theory calculations suggested graviquinone as a kinetic product of pcm-scavenging •OH radicals. Our results demonstrate the pharmacological value of an in situ-formed, oxidative stress-related metabolite of an antioxidant. This might be of particular importance for designing new strategies for antioxidant-based drug discovery.
- MeSH
- antitumorózní látky farmakologie toxicita MeSH
- chemorezistence účinky léků MeSH
- cyklohexanony farmakologie toxicita MeSH
- hydroxylový radikál chemie MeSH
- kyseliny kumarové chemie metabolismus farmakologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- objevování léků MeSH
- oxidace-redukce MeSH
- počítačová simulace MeSH
- poškození DNA účinky léků MeSH
- scavengery volných radikálů farmakologie toxicita MeSH
- signální transdukce účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The aim of study was to review the status of arterial pH, pO(2) and pCO(2) under general anesthesias in dependence on the light-dark (LD) cycle in spontaneously breathing rats. The experiments were performed using three- to four-month-old pentobarbital(P)-, ketamine/xylazine(K/X)- and zoletil(Z)-anesthetized female Wistar rats after a four-week adaptation to an LD cycle (12 h light:12 h dark). The animals were divided into three experimental groups according to the anesthetic agent used: P (light n=11; dark n=8); K/X (light n=13; dark n=11); and Z (light n=18; dark n=26). pH and blood gases from arterial blood were analyzed. In P anesthesia, LD differences in pH, pO(2), and pCO(2) were eliminated. In K/X anesthesia, parameters showed significant LD differences. In Z anesthesia, LD differences were detected for pH and pO(2) only. Acidosis, hypoxia, and hypercapnia have been reported for all types of anesthesia during the light period. In the dark period, except for P anesthesia, the environment was more stable and values fluctuated within normal ranges. From a chronobiological perspective, P anesthesia was not the most appropriate type of anesthesia in these rat experiments. It eliminated LD differences, and also produced a more acidic environment and more pronounced hypercapnia than K/X and Z anesthesias.
- MeSH
- analýza krevních plynů metody MeSH
- anestetika celková škodlivé účinky krev farmakologie MeSH
- celková anestezie * škodlivé účinky trendy MeSH
- chronobiologické jevy účinky léků fyziologie MeSH
- fixní kombinace léků MeSH
- hyperkapnie krev chemicky indukované MeSH
- hypoxie krev chemicky indukované MeSH
- ketamin škodlivé účinky farmakologie MeSH
- krysa rodu rattus MeSH
- pentobarbital škodlivé účinky farmakologie MeSH
- potkani Wistar MeSH
- tiletamin škodlivé účinky farmakologie MeSH
- zolazepam škodlivé účinky farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
A new designer drug, a dissociative anesthetic, and a putative N-methyl-D-aspartate receptor antagonist, methoxetamine (MXE) noted by the EU Early Warning System has been already identified as a cause of several fatalities worldwide. The primary objective of this work was to develop a suitable sample preparation method allowing for isolation of MXE and its main metabolites in high yields from rat brain, liver, and lungs. For the purpose of the project, MXE and five metabolites were synthesized in-house, specifically O-desmethyl-normethoxetamine, O-desmethylmethoxetamine, dihydro-O-desmethylmethoxetamine, normethoxetamine, and dihydromethoxetamine. A sample preparation procedure consisted in the homogenization of the tissue applying salting-out-assisted liquid-liquid extraction (SALLE). A subsequent liquid chromatography-mass spectrometry (LC-MS) analysis was based on reversed-phased chromatography hyphenated with a triple quad MS system in a positive electrospray mode. Multiple reaction monitoring (MRM) was used for qualification and quantification of the analytes. The quantification was based on the application of an isotopically labeled internal standard, normethoxetamine-d3. The matrix-matched calibrations were prepared for each type of matrix with regression coefficients 0.9943-1.0000. The calibration curves were linear in the concentration range of 2.5-250 ng g(-1). Limits of quantification (LOQs) were estimated as 2.5 and 5 ng g(-1), respectively. Recovery (80-117%) and matrix effect (94-110%) at 100 ng g(-1) and intra- and inter-day accuracy and precision at low (2.5 ng g(-1)), middle (25 ng g(-1)), and upper (250 ng g(-1)) concentration levels for all the analytes in all three types of tissues were also determined. The developed analytical method was applied to a set of real samples gathered in toxicological trials on rats and MXE, and its metabolites were determined successfully.
- MeSH
- chromatografie kapalinová metody MeSH
- cyklohexanony analýza metabolismus farmakokinetika MeSH
- cyklohexylaminy analýza metabolismus farmakokinetika MeSH
- extrakce kapalina-kapalina metody MeSH
- játra chemie MeSH
- kalibrace MeSH
- krysa rodu rattus MeSH
- limita detekce MeSH
- mozek - chemie MeSH
- nové syntetické drogy analýza MeSH
- plíce chemie MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- zoletilová anestezie,
- MeSH
- acidobazická rovnováha MeSH
- anxiolytika MeSH
- chronobiologické jevy * MeSH
- elektrokardiografie MeSH
- interpretace statistických dat MeSH
- modely u zvířat MeSH
- potkani Wistar MeSH
- tělesná teplota MeSH
- tiletamin terapeutické užití MeSH
- zolazepam terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
Methoxetamine (MXE) is a novel psychoactive compound (NPS) that emerged in 2010 as a substitute for the dissociative anaesthetic ketamine. MXE has a reputation of carrying a lower risk of harm than ketamine, however a number of deaths have been reported. Currently very little is known about the psychopharmacological effects of this compound or its toxicity; therefore we tested, in Wistar rats, the effects of MXE in a series of behavioural tasks, measured its pharmacokinetics and urinary metabolites. Locomotor activity and its spatial characteristics (in the open field) and sensorimotor gating (prepulse inhibition; PPI) were evaluated after 5, 10 and 40mg/kg subcutaneous (sc.) MXE. Pharmacokinetics and brain: serum ratios were evaluated after 10mg/kg sc. MXE so that peak drug concentration data could be used to complement interpretation of maximal behavioural effects. Finally, quantification of metabolites in rat urine collected over 24h was performed after single bolus of MXE 40mg/kg sc. 5 and 10mg/kg MXE induced significant locomotor stimulation, in addition it increased thigmotaxis and decreased time spent in the centre of the open field (indicative of anxiogenesis). By contrast, 40mg/kg reduced locomotion and increased time spent in the centre of the arena, suggesting sedation/anaesthesia or stereotypy. The duration of effects was present for at least 60-90min, although for 5mg/kg, locomotion diminished after 60min. MXE decreased baseline acoustic startle response (ASR) and disrupted PPI, irrespective of testing-onset. MXE (all doses) reduced habituation but only at 60min. Maximal brain levels of MXE were observed 30min after administration, remained high at 60min and progressively declined to around zero after six hours. MXE accumulated in the brain; the brain: serum ratio was between 2.06 and 2.93 throughout the whole observation. The most abundant urinary metabolite was O-desmethylmethoxetamine followed by normethoxetamine. To conclude, MXE acts behaviourally as a typical dissociative anaesthetic with stimulant and anxiogenic effects at lower doses, sedative/anaesthetic effects at higher doses, and as a disruptor of sensorimotor gating. Its duration of action exceeds that of ketamine which is consistent with reports from MXE users. The accumulation of the drug in brain tissue might reflect MXE's stronger potency compared to ketamine and indicate increased toxicity.
- MeSH
- akustická stimulace MeSH
- cyklohexanony metabolismus farmakologie MeSH
- cyklohexylaminy metabolismus farmakologie MeSH
- krysa rodu rattus MeSH
- lokomoce účinky léků MeSH
- mozek účinky léků metabolismus MeSH
- pátrací chování účinky léků MeSH
- potkani Wistar MeSH
- prepulsní inhibice účinky léků MeSH
- psychotropní léky metabolismus farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Klíčová slova
- Orfadin,
- MeSH
- benzoáty terapeutické užití MeSH
- biologické markery MeSH
- cyklohexanony terapeutické užití MeSH
- dieta MeSH
- genetické testování metody využití MeSH
- hepatocelulární karcinom terapie MeSH
- hypoglykemie diagnóza terapie MeSH
- klinický obraz nemoci MeSH
- kojenec MeSH
- komorbidita MeSH
- lidé MeSH
- prognóza MeSH
- statistika jako téma MeSH
- transplantace jater * MeSH
- tyrosinemie * diagnóza genetika terapie MeSH
- ultrasonografie metody využití MeSH
- vrozené poruchy metabolismu diagnóza etiologie genetika MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- Klíčová slova
- beloranib hemioxalát,
- MeSH
- Aspergillus fumigatus MeSH
- benzochinony terapeutické užití MeSH
- cyklohexanony terapeutické užití MeSH
- inhibitory enzymů * aplikace a dávkování farmakokinetika škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- mykotoxiny analogy a deriváty terapeutické užití MeSH
- obezita * farmakoterapie MeSH
- Praderův-Williho syndrom farmakoterapie MeSH
- Check Tag
- lidé MeSH
BACKGROUND: Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data. METHODS: Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications. RESULTS: Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 μM) and NTBC-levels in the therapeutic range (20-40 μM). Side effects of NTBC are mild and often transient. Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood). CONCLUSION: Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.
- MeSH
- cyklohexanony škodlivé účinky terapeutické užití MeSH
- dítě MeSH
- inhibitory enzymů škodlivé účinky terapeutické užití MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- následné studie MeSH
- nitrobenzoany škodlivé účinky terapeutické užití MeSH
- novorozenec MeSH
- novorozenecký screening metody MeSH
- předškolní dítě MeSH
- průřezové studie MeSH
- průzkumy a dotazníky MeSH
- renální insuficience diagnóza chirurgie MeSH
- retrospektivní studie MeSH
- selhání jater diagnóza chirurgie MeSH
- transplantace jater MeSH
- tyrosinemie diagnóza terapie MeSH
- výsledek terapie MeSH
- vzácné nemoci diagnóza farmakoterapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
